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We found that GroEL in Porphyromonas gingivalis accelerated tumor growth and increased mortality in tumor‐bearing mice; GroEL promoted proangiogenic function, which may be the reason for promoting tumor growth. To understand the regulatory mechanisms by which GroEL increases the proangiogenic function of endothelial progenitor cells (EPCs), we explored in this study. In EPCs, MTT assay, wound‐healing assay, and tube formation assay were performed to analyze its activity. Western blot and immunoprecipitation were used to study the protein expression along with next‐generation sequencing for miRNA expression. Finally, a murine tumorigenesis animal model was used to confirm the results of in vitro. The results indicated that thrombomodulin (TM) direct interacts with PI3K/Akt to inhibit the activation of signaling pathways. When the expression of TM is decreased by GroEL stimulation, molecules in the PI3K/Akt signaling axis are released and activated, resulting in increased migration and tube formation of EPCs. In addition, GroEL inhibits TM mRNA expression by activating miR‐1248, miR‐1291, and miR‐5701. Losing the functions of miR‐1248, miR‐1291, and miR‐5701 can effectively alleviate the GroEL‐induced decrease in TM protein levels and inhibit the proangiogenic abilities of EPCs. These results were also confirmed in animal experiments. In conclusion, the intracellular domain of the TM of EPCs plays a negative regulatory role in the proangiogenic capabilities of EPCs, mainly through direct interaction between TM and PI3K/Akt to inhibit the activation of signaling pathways. The effects of GroEL on tumor growth can be reduced by inhibiting the proangiogenic properties of EPCs through the inhibition of the expression of specific miRNAs. [ABSTRACT FROM AUTHOR]

Orthotopic allograft transplantation (OAT) is a significant approach to addressing organ failure. However, persistent immune responses to the allograft affect chronic rejection, which induces OAT vasculopathy (OATV) and organ failure. Porphyromonas gingivalis can infiltrate remote organs via the bloodstream, thereby intensifying the severity of cardiovascular, respiratory, and neurodegenerative diseases and cancer. GroEL, a virulence factor of P. gingivalis promotes pro‐inflammatory cytokine production in host cells, which assumes to play a pivotal role in the pathogenesis of cardiovascular diseases. Although the aggravation of OATV is attributable to numerous factors, the role of GroEL remains ambiguous. Therefore, this study aimed to investigate the impact of GroEL on OATV. Aortic grafts extracted from PVG/Seac rats were transplanted into ACI/NKyo rats and in vitro human endothelial progenitor cell (EPC) and coronary artery endothelial cell (HCAEC) models. The experimental findings revealed that GroEL exacerbates OATV in ACI/NKyo rats by affecting EPC and smooth muscle progenitor cell (SMPC) function and enabling the anomalous accumulation of collagen. In vitro, GroEL spurs endothelial‐mesenchymal transition in EPCs, reduces HCAEC tube formation and barrier function by downregulating junction proteins, accelerates HCAEC aging by lowering mitochondrial membrane potential and respiratory function, and impedes HCAEC migration by modulating cytoskeleton‐associated molecules. This study suggests that P. gingivalis GroEL could potentially augment OATV by impacting vascular progenitor and endothelial cell functions. [ABSTRACT FROM AUTHOR]

The homeostasis of intracellular pH (pHi) affects many cellular functions. Our previous study has established a functional and molecular model of the active pHi regulators in human induced pluripotent stem cells (hiPSCs). The aims of the present study were to further quantify passive pHi buffering power (β) and to investigate the effects of extracellular pH and Na+–H+ exchanger 1 (NHE1) activity on pluripotency in hiPSCs. pHi was detected by microspectrofluorimetry with pH‐sensitive dye‐BCECF. Western blot, immunofluorescence staining, and flow cytometry were used to detect protein expression and pluripotency. Our study in hiPSCs showed that (a) the value of total (βtot), intrinsic (βi), and CO2‐dependent (βCO2) buffering power all increased while pHi increased; (b) during the spontaneous differentiation for 4 days, the β values of βtot and βCO2 changed in a tendency of decrease, despite the absence of statistical significance; (c) an acidic cultured environment retained pluripotency and further upregulated expression and activity of NHE1 during spontaneous differentiation; (d) inhibition on NHE1 activity promoted the loss of pluripotency. In conclusion, we, for the first time, established a quantitative model of passive β during differentiation and demonstrated that maintenance of NHE1 at a higher level was of critical importance for pluripotency retention in hiPSCs. [ABSTRACT FROM AUTHOR]

Background and Purpose: Atherosclerosis, resulting from lipid dysregulation and vascular inflammation, causes atherosclerotic cardiovascular disease (ASCVD), which contributes to morbidity and mortality worldwide. Chalcone and its derivatives possess beneficial properties, including anti‐inflammatory, antioxidant and antitumour activity with unknown cardioprotective effects. We aimed to develop an effective chalcone derivative with antiatherogenic potential. Experimental Approach Human THP‐1 cells and HUVECs were used as in vitro models. Western blots and real‐time PCRs were performed to quantify protein, mRNA and miRNA expressions. The cholesterol efflux capacity was assayed by 3H labelling of cholesterol. LDL receptor knockout (Ldlr−/−) mice fed a high‐fat diet were used as an in vivo atherogenesis model. Haematoxylin and eosin and oil red O staining were used to analyse plaque formation. Key Results: Using ATP‐binding cassette transporter A1 (ABCA1) expression we identified the chalcone derivative, 1m‐6, which enhances ABCA1 expression and promotes cholesterol efflux in THP‐1 macrophages. Moreover, 1m‐6 stabilizes ABCA1 mRNA and suppresses the expression of potential ABCA1‐regulating miRNAs through nuclear factor erythroid 2‐related factor 2 (Nrf2)/haem oxygenase‐1 (HO‐1) signalling. Additionally, 1m‐6 significantly inhibits TNF‐α‐induced expression of adhesion molecules, vascular cell adhesion molecule 1 (VCAM‐1) and intercellular adhesion molecule 1 (ICAM‐1), plus production of proinflammatory cytokines via inhibition of JAK/STAT3 activation and the modulation of Nrf2/HO‐1 signalling in HUVECs. In atherosclerosis‐prone mice, 1m‐6 significantly reduces lipid accumulation and atherosclerotic plaque formation. Conclusion and Implications: Our study demonstrates that 1m‐6 produces promising atheroprotective effects by enhancing cholesterol efflux and suppressing inflammation‐induced endothelial dysfunction, which opens a new avenue for treating ASCVD. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc [ABSTRACT FROM AUTHOR]

This study addressed the hypothesis that cardiac Sirtuin 1 (Sirt1) deficiency alters cardiomyocyte Ca2+ and Na+ regulation, leading to cardiac dysfunction and arrhythmogenesis. We used mice with cardiac‐specific Sirt1 knockout (Sirt1−/−). Sirt1flox/flox mice were served as control. Sirt1−/− mice showed impaired cardiac ejection fraction with increased ventricular spontaneous activity and burst firing compared with those in control mice. The arrhythmic events were suppressed by KN93 and ranolazine. Reduction in Ca2+ transient amplitudes and sarcoplasmic reticulum (SR) Ca2+ stores, and increased SR Ca2+ leak were shown in the Sirt1−/− mice. Electrophysiological measurements were performed using patch‐clamp method. While L‐type Ca2+ current (ICa, L) was smaller in Sirt1−/− myocytes, reverse‐mode Na+/Ca2+ exchanger (NCX) current was larger compared with those in control myocytes. Late Na+ current (INa, L) was enhanced in the Sirt1−/− mice, alongside with elevated cytosolic Na+ level. Increased cytosolic and mitochondrial reactive oxygen species (ROS) were shown in Sirt1−/− mice. Sirt1−/− cardiomyocytes showed down‐regulation of L‐type Ca2+ channel α1c subunit (Cav1.2) and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a), but up‐regulation of Ca2+/calmodulin‐dependent protein kinase II and NCX. In conclusions, these findings suggest that deficiency of Sirt1 impairs the regulation of intracellular Ca2+ and Na+ in cardiomyocytes, thereby provoking cardiac dysfunction and arrhythmogenesis. [ABSTRACT FROM AUTHOR]

Cardiovascular complications are leading causes of morbidity and mortality in patients with chronic kidney disease (CKD). CKD significantly affects cardiac calcium (Ca2+) regulation, but the underlying mechanisms are not clear. The present study investigated the modulation of Ca2+ homeostasis in CKD mice. Echocardiography revealed impaired fractional shortening (FS) and stroke volume (SV) in CKD mice. Electrocardiography showed that CKD mice exhibited longer QT interval, corrected QT (QTc) prolongation, faster spontaneous activities, shorter action potential duration (APD) and increased ventricle arrhythmogenesis, and ranolazine (10 µmol/L) blocked these effects. Conventional microelectrodes and the Fluo‐3 fluorometric ratio techniques indicated that CKD ventricular cardiomyocytes exhibited higher Ca2+ decay time, Ca2+ sparks, and Ca2+ leakage but lower [Ca2+]i transients and sarcoplasmic reticulum Ca2+ contents. The CaMKII inhibitor KN93 and ranolazine (RAN; late sodium current inhibitor) reversed the deterioration in Ca2+ handling. Western blots revealed that CKD ventricles exhibited higher phosphorylated RyR2 and CaMKII and reduced phosphorylated SERCA2 and SERCA2 and the ratio of PLB‐Thr17 to PLB. In conclusions, the modulation of CaMKII, PLB and late Na+ current in CKD significantly altered cardiac Ca2+ regulation and electrophysiological characteristics. These findings may apply on future clinical therapies. [ABSTRACT FROM AUTHOR]

This large‐scale case‐control study in Taiwan elucidated the potential connection between fibrate use and liver cancer by using the Longitudinal Health Insurance Database 2005 with a propensity‐score–matching design. In total, 4173 patients diagnosed as having liver cancer were included as cases, and 4173 propensity‐score–matched patients without liver cancer were identified as controls. The association between previous fibrate use and liver cancer occurrence was demonstrated using conditional logistic regression. Fibrate use was noted in 371 (8.89%) cases and 481 (11.53%) controls. After adjustments, the cases had significantly lower odds of previous fibrate use than did the controls (adjusted odds ratio 0.70, 95%CI 0.60‐0.82); moreover, regardless of the patients' sex, age group, and comorbidities, the cases were less likely to have used fibrates than were the controls. Dose‐dependent analysis revealed that 1‐695 cumulative defined daily doses of fibrates may significantly induce a protective effect for liver cancer. Although other fibrate dose intervals did not reach statistical significance, the dose‐response curve presented the trend of a protective effect for liver cancer among the fibrate users. In summary, fibrate use had a significant protective effect against liver cancer in this Asian population. [ABSTRACT FROM AUTHOR]

Background: The presence of intracellular pH (pHi) regulators, including Na+-H+exchanger (NHE), Na+-HCO-3 co-transporter (NBC), Cl-/OH- exchanger (CHE), and Cl-/HCO-3 exchanger (AE), have been confirmed in many mammalian cells. Alcohol consumption is associated with increased risk of cardiovascular disorder. The aims of the study were to identify the possible transmembrane pHi regulators and to explore the effects of ethanol (EtOH) (10 to 300 mM) on the resting pHi and pHi regulators in human aorta smooth muscle cells (HASMCs). Methods: HASMCs were obtained from patients undergoing heart transplant. The pHi was measured by microspectrofluorimetry with the pH-sensitive dye, BCECF-AM. Results: The following results are obtained. (i) In cultured HASMCs, the resting pHi was 7.19 ± 0.04 and 7.13 ± 0.02 for HEPES- and CO2/HCO-3-buffered solution, respectively. (ii) Two different Na+-dependent acid-equivalent extruders, including NHE and Na+-coupled HCO-3 transporter, functionally coexisted. (iii) Two different Cl--dependent acid loaders (CHE and AE) were functionally identified. (iv) EtOH induced a biphasic, concentration-dependent change in resting pHi (+0.25 pH unit at 100 mM but only +0.05 pH unit at 300 mM) in bicarbonate-buffered solution, while caused a concentration-dependent decrease in resting pHi (-0.06 pH unit at 300 mM) in HEPES-buffered solution. (v) The effect of EtOH on NHE activity was also biphasic: increase of 40% at lower concentration of 10 mM, followed by decrease of 30% at higher concentration of 300 mM. (vi) The increase in Na+-coupled HCO-3 transporter activity by EtOH was concentration dependent. (vii) The effect of EtOH on CHE and AE activities was both biphasic: increase of ~25% at 30 mM, followed by decrease of 10 to 25%at 100 mM, and finally increase of 15 to 20%at 300 mM. Conclusions: This study demonstrated that 2 acid extruders and 2 acid loaders coexisted functionally in HASMCs and that EtOH induced a biphasic, concentration-dependent change in resting pHi by altering the activity of the 2 acid extruders, NHE and Na+-coupled HCO-3 transporter, and the 2 acid loaders, CHE and AE. [ABSTRACT FROM AUTHOR]

Yang H-Y, Lin C-Y, Tsai Y-T, Lee C-Y, Tsai C-S. Experience of heart transplantation from hemodynamically unstable brain-dead donors with extracorporeal support. Abstract: The shortage of organ donors remains a major problem for transplantation worldwide. Potential donors after brain death may become hemodynamically unstable, despite maximal medical management, which ultimately leads to failure of organ procurement. We reviewed the medical records of five brain-dead potential donors who presented with hemodynamic instability despite maximal medical management that were supported by extracorporeal circulation membrane oxygenation (ECMO). The outcomes of heart recipients were reviewed. The five donors under extracorporeal support finished a declaration of brain death without cardiac arrest. Donor organs, including three hearts, nine kidneys, and four livers, were harvested from the five donors under ECMO support. All three heart recipients recovered uneventfully after one yr of follow-up. Our experience indicates that potential donors may experience central-failure-related hemodynamic instability after brain death, despite maximal medical support, which leads to a fatal result. Beyond medical management, prompt and early extracorporeal support for salvaging brain-dead potential donors from cardiac death seems to be a practical strategy to increase the donor pool and preserve donor organs. [ABSTRACT FROM AUTHOR]

Infection is a known cause of abdominal aortic aneurysm (AAA), and matrix metalloproteases‐2 (MMP‐2) secreted by vascular smooth muscle cells (SMCs) plays a key role in the structural disruption of the middle layer of the arteries during AAA progression. The periodontal pathogen Porphyromonas gingivalis is highly associated with the progression of periodontitis. GroEL protein of periodontal pathogens is an important virulence factor that can invade the body through either the bloodstream or digestive tract and is associated with numerous systemic diseases. Although P. gingivalis aggravates AAA by increasing the expression of MMP‐2 in animal studies, the molecular mechanism through which P. gingivalis regulates the expression of MMP‐2 is still unknown and requires further investigation.In this study, we first confirmed through animal experiments that P. gingivalis GroEL promotes MMP‐2 secretion from vascular SMCs, thereby aggravating Ang II‐induced aortic remodeling and AAA formation. In addition, rat vascular SMCs and A7r5 cells were used to investigate the underlying mechanisms in vitro. The results demonstrated that GroEL can promote the interaction between the K639 site of MMP‐2 and SUMO‐1, leading to MMP‐2 SUMOylation, which inhibits the reoccurrence of non–K639‐mediated monoubiquitylation. Hence, the monoubiquitylation‐mediated lysosomal degradation of MMP‐2 is inhibited, consequently promoting MMP‐2 stability and production. SUMOylation may facilitate intra‐endoplasmic reticulum (ER) and Golgi trafficking of MMP‐2, thereby enhancing its transport capacity. In conclusion, this is the first report demonstrating the presence of a novel posttranslational modification, SUMOylation, in the MMP family, suggesting that P. gingivalis GroEL may exacerbate AAA formation by increasing MMP‐2 production through SUMOylation in vascular SMCs. This study also provides a novel perspective on the role of SUMOylation in MMP‐2–induced systemic diseases. [ABSTRACT FROM AUTHOR]

Background: The use of cardiopulmonary bypass (CPB) during coronary artery bypass grafting (CABG) is associated with substantial morbidity and mortality, especially in the elderly. The purpose of this study was to evaluate the feasibility of beating heart coronary artery revascularization in patients aged at least 80 years. Methods: A retrospective chart review was carried out for 17 patients aged over 80 years who underwent isolated off-pump CABG at the Tri-Service General Hospital, Taiwan, during the period July 1999 to December 2000. The demographic characteristics, operative data, postoperative results and short-term outcomes of patients were compared with those of 12 patients who underwent conventional CABG using CPB during the same time period. Results: The off-pump group consisted of 13 men and four women with a mean age of 82.2 ± 0.9 years and an ejection fraction of 53.4 ± 4.1%. The on-pump group consisted of eight men and four women with a mean age of 83.5 ± 0.5 and an ejection fraction of 42.0 ± 4.8%. The mean number of anastomoses performed per patient was 3.1 ± 0.3 in the off-pump group and 3.0 ± 0.14 in the on-pump group. There was no occurrence of stroke, myocardial infarction, re-entry for bleeding or renal failure among patients in the off-pump group. Intubation time (10.6 vs 48.4 h), intensive care unit stay (2.9 vs 4.2 days) and postoperative stay (12.7 vs 18.1 days) were significantly shorter in the off-pump group than in the on-pump group. No patient died in the off-pump group, whereas one patient died in the on-pump group. Conclusions: The results of this study suggest that the off-pump technique is a safe and efficacious method for myocardial revascularization in elderly patients and that the short-term outcome obtained with this technique are promising. Our data suggest that the off-pump technique is preferable in these patients. [ABSTRACT FROM AUTHOR]

This study addressed the hypothesis that cardiac Sirtuin 1 (Sirt1) deficiency alters cardiomyocyte Ca 2+ and Na + regulation, leading to cardiac dysfunction and arrhythmogenesis. We used mice with cardiac-specific Sirt1 knockout (Sirt1 -/- ). Sirt1 flox/flox mice were served as control. Sirt1 -/- mice showed impaired cardiac ejection fraction with increased ventricular spontaneous activity and burst firing compared with those in control mice. The arrhythmic events were suppressed by KN93 and ranolazine. Reduction in Ca 2+ transient amplitudes and sarcoplasmic reticulum (SR) Ca 2+ stores, and increased SR Ca 2+ leak were shown in the Sirt1 -/- mice. Electrophysiological measurements were performed using patch-clamp method. While L-type Ca 2+ current (I Ca, L ) was smaller in Sirt1 -/- myocytes, reverse-mode Na + /Ca 2+ exchanger (NCX) current was larger compared with those in control myocytes. Late Na + current (I Na, L ) was enhanced in the Sirt1 -/- mice, alongside with elevated cytosolic Na + level. Increased cytosolic and mitochondrial reactive oxygen species (ROS) were shown in Sirt1 -/- mice. Sirt1 -/- cardiomyocytes showed down-regulation of L-type Ca 2+ channel α1c subunit (Cav1.2) and sarcoplasmic/endoplasmic reticulum Ca 2+  ATPase 2a (SERCA2a), but up-regulation of Ca 2+ /calmodulin-dependent protein kinase II and NCX. In conclusions, these findings suggest that deficiency of Sirt1 impairs the regulation of intracellular Ca 2+ and Na + in cardiomyocytes, thereby provoking cardiac dysfunction and arrhythmogenesis., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Streptococcal bacteremia is an uncommon presentation for colorectal malignancy, yet most physicians would probably be aware of the association between Streptococcus bovis infection and such malignancy; however, many physicians may be unaware that other streptococcal species are also associated with colon and rectal cancers. We describe a 62-year-old male with adenocarcinoma of the sigmoid colon with the presentation of infective endocarditis due to infection by Streptococcus viridans, and we also report on the condition's successful treatment.

Background: Disturbances in intracellular pH (pHi) of the heart can trigger major changes in the strength and rhythm of the heartbeat. It is well known that two extruders, Na+/H+ exchange (NHE) and Na+/HCO3- symporter (NHS), and a monocarboxylic acid transporter (MCT) are involved in acid-equivalent extruding in the human heart. Drinking alcohol has been proven to affect blood pressure and heart contractility and, sometimes, causes cardiac arrhythmia. To assess the effects of alcohol on pHi regulators and electromechanical parameters, various concentrations of alcohol were superfused into human myocardium in the present study., Methods: Human atrial myocardium was obtained from hearts of patients undergoing corrective cardiac surgery. Institutional rules for the protection of human subjects were observed. In the whole study, pHi was measured by an epifluorescent, ratiometric microspectrofluorimetry technique with the dye BCECF, while electrophysiological experiments were performed by traditional micropipette. NHE and NHS activities were measured after pHi recovery from intracellular acidosis induced by NH4Cl prepulse, while MCT activity was measured by a lactate adding/removing technique., Results: In pHi experiments, we demonstrated that alcohol could induce a biphasic, concentration-dependent (30-1000 mM) pHi change (i.e., alkalosis after acidosis) in human atrium in HEPES-buffered Tyrode solution. To a smaller extent, similar results were found when the superfusate was replaced by HCO3- -buffered Tyrode solution. NHE activity was increased by a moderate concentration of alcohol (30 mM), while it was inhibited in a concentration-dependent manner by higher concentrations of alcohol (>100 mM). On the contrary, 30-1000 mM alcohol increased the activity of NHS in a concentration-dependent manner. Surprisingly, MCT activity was not affected by alcohol. In electromechanical experiments, we found that alcohol (30-1000 mM) had a notable concentration-dependent inhibitory effect on the contractile force, while higher concentrations of alcohol (>100 mM) decreased the action potential amplitude, upstroke velocity, duration of repolarization, and force of contractions in a concentration-dependent way. All these alcohol-induced pHi changes and electromechanical inhibitions were reversible., Conclusions: To our knowledge, this study provides the first evidence that alcohol can affect pHi in human myocardial tissue by changing the activity of acid extruders (i.e., NHE and NHS).

Background and Aim of the Study: Rupture of the sinus of Valsalva is rare, and there is a higher incidence of such rupture in Oriental countries than elsewhere. The objective of this study is to present the pathologic features and the clinical outcome after surgery in such patients., Methods: Between 1980 and 2001, a total of 17 patients (15 males and 2 females) with ruptured aneurysm of sinus of Valsalva underwent surgical intervention at the Tri-Service General Hospital, Taiwan. Their age ranged from 22 to 59 years with a mean of 33.5 years. These surgical operations made up 0.51% of the total cardiac operations (3305) performed during this period. The medical records were retrospectively reviewed., Results: The origin of the ruptured aneurysm of the sinus of Valsalva was the right coronary sinus in 12 patients, the noncoronary sinus in 4, and the left coronary sinus in one patient. The aneurysms ruptured into the right ventricle in 12 patients, into the right atrium in 3 patients, and into the left ventricle in 2 patients. Associated cardiac anomalies were aortic regurgitation in eight patients, ventricular septal defect in seven, and coronary artery fistula in one patient. There was no early postoperative death and one patient underwent a second operation after aneurysm of the sinus of Valsalva (ASV) relapse., Conclusions: The operation for a ruptured aneurysm of sinus of Valsalva carries a low operative risk and results in excellent long-term survival after surgical treatment.